Perirenal Fat Promotes Renal Arterial Endothelial Dysfunction in Obese Swine through Tumor Necrosis Factor-α

Abstract

Purpose Perirenal fat is associated with poor blood pressure control and chronic kidney disease, but the underlying mechanisms remain elusive. We tested the hypothesis that perirenal fat impairs renal arterial endothelial function in pigs with obesity-metabolic derangements (ObM). Material and Methods Fourteen domestic pigs were studied after 16 weeks of a high-fat/high-fructose diet (ObM) or standard chow (Lean). Renal blood flow (RBF), glomerular filtration rate (GFR), and visceral fat volumes were studied in-vivo with CT. Renal arterial endothelial function was also studied ex-vivo in the organ bath. Results ObM pigs demonstrated increased body weight, blood pressure, cholesterol, and intra-abdominal fat compared to lean pigs, and perirenal fat volume was significantly larger. RBF and GFR were markedly elevated, while urinary protein level was preserved. Ex-vivo acetylcholine-induced endothelium-dependent vasodilation of renal artery rings was substantially impaired in ObM compared to Lean. Endothelial function was further blunted in both ObM and Lean arterial rings by incubation with perirenal fat harvested from ObM, but not from Lean pigs, and was restored by inhibition of tumor necrosis factor (TNF)-α. ObM perirenal fat also showed increased pro-inflammatory macrophage infiltration and TNF-α expression. Conclusions ObM perirenal fat directly causes renal artery endothelial dysfunction, partly mediated by TNF-α.

Investigating the Metabolic Syndrome

“…(Pawar et al , 2015, Ma et al , 2015) In domestic pigs, a 2% high-cholesterol diet causes only endothelial dysfunction and early changes of atherosclerosis, but not obesity, IR, or hypertension (Eirin et al , 2014, Urbieta-Caceres et al , 2010). Contrarily, a 3–4 months ad-libitum high-fat/high-fructose diet (Table 1) induced significant manifestations of MetS resembling those observed in Ossabaw pigs.…”

“…Both Mets Ossabaw and domestic pig models almost double their RBF and GFR upon MetS diet feeding (Li et al , 2011, Ma et al , 2015). In Ossabaw pigs, the augmented renal hemodynamic indices are associated with increased renal cortical volume and microvascular density (Li et al , 2012), linking augmented hemodynamics and microcirculatory remodeling in the development of kidney hypertrophy (Li et al , 2011).…”

“…By 16 weeks of diets, MetS Ossabaw pigs exhibited increased renal inflammatory macrophages and plasma ox-LDL levels (Zhang et al , 2013), indicating that inflammation may play a role at later stages of renal injury. Both MetS Ossabaw and domestic pig kidneys are also encased in greater amounts of perirenal fat compared with control kidneys, enriched in inflammatory macrophages and cytokines, including TNF-α(Zhang et al , 2013, Ma et al , 2015). At least in the domestic pig MetS model, the peri-renal fat may not only serve as an inflammatory depot but may also impair renal artery endothelial function (Ma et al , 2015).…”

“…Both MetS Ossabaw and domestic pig kidneys are also encased in greater amounts of perirenal fat compared with control kidneys, enriched in inflammatory macrophages and cytokines, including TNF-α(Zhang et al , 2013, Ma et al , 2015). At least in the domestic pig MetS model, the peri-renal fat may not only serve as an inflammatory depot but may also impair renal artery endothelial function (Ma et al , 2015). These findings may have implications in the setting of therapeutic management of MetS-induced kidney disease.…”

“…The adipokines adiponectin and leptin are reciprocally regulated by obesity (Spurlock et al , 1998, Jacobi et al , 2004, Pawar et al , 2015). Indeed, MetS upregulates in porcine adipose tissue the release of abundant inflammatory adipokines from the adipose tissue, such as TNF-α, interleukin-6, and monocyte chemotactic protein-1 (Pawar et al , 2015), and stimulates macrophage infiltration (Ma et al , 2015, Zhang et al , 2013). Furthermore, MetS upregulates the expression of toll-like receptor in porcine adipose tissue (Gabler et al , 2008), which is closely associated with development of IR (Shi et al , 2006).…”